Physiologic Adaptation to Macronutrient Change Distorts Findings from Short Dietary Trials: Reanalysis of a Metabolic Ward Study.

An influential 2-wk cross-over feeding trial without a washout period purported to show advantages of a low-fat diet (LFD) compared with a low-carbohydrate diet (LCD) for weight control. In contrast to several other macronutrient trials, the diet order effect was originally reported as not significant. In light of a new analysis by the original investigative group identifying an order effect, we aimed to examine, in a reanalysis of publicly available data (16 of 20 original participants; 7 female; mean BMI, 27.8 kg/m2), the validity of the original results and the claims that trial data oppose the carbohydrate-insulin model of obesity (CIM). We found that energy intake on the LCD was much lower when this diet was consumed first compared with second (a difference of -1164 kcal/d, P = 3.6 × 10-13); the opposite pattern was observed for the LFD (924 kcal/d, P = 2.0 × 10-16). This carry-over effect was significant (P interaction = 0.0004) whereas the net dietary effect was not (P = 0.4). Likewise, the between-arm difference (LCD - LFD) was -320 kcal/d in the first period and +1771 kcal/d in the second. Body fat decreased with consumption of the LCD first and increased with consumption of this diet second (-0.69 ± 0.33 compared with 0.57 ± 0.32 kg, P = 0.007). LCD-first participants had higher ß-hydroxybutyrate levels while consuming the LCD and lower respiratory quotients while consuming LFD when compared with LFD-first participants on their respective diets. Change in insulin secretion as assessed by C-peptide in the first diet period predicted higher energy intake and less fat loss in the second period. These findings, which tend to support rather than oppose the CIM, suggest that differential (unequal) carry-over effects and short duration, with no washout period, preclude causal inferences regarding chronic macronutrient effects from this trial.

Association between dairy products consumption and the prevalences of combined prediabetes and type 2 diabetes mellitus in Brazilian adolescents: a cross-sectional study.

The association between dairy products consumption in adults and the likelihood of type 2 diabetes mellitus (T2DM) has been described, but more information on the adolescent population is needed. This nationally representative, cross-sectional school-based study aimed to describe the consumption of dairy products and their subtypes and to evaluate their association with prediabetes and T2DM in adolescents. The Study of Cardiovascular Risks in Adolescents (ERICA) includes adolescents aged 12-17 years. Dairy products consumption was evaluated by 24-h food recall. Associations with fasting glucose, glycated hemoglobin (HbA1c) and insulin resistance, as measured by homeostatic model assessment-insulin resistance (HOMA-IR), were evaluated by multivariate linear regression. Poisson regression was also used to assess the association between dairy products consumption and the combined prevalence of prediabetes and T2DM. Models were adjusted for sociodemographic, nutritional, behavioural and anthropometrics. The final sample analysed consisted of 35 614 adolescents. Total intake of dairy products was inversely associated with fasting blood glucose levels after adjusting for all covariates (ß = -0·452, 95 % CI -0·899, -0·005). The associations were stronger for overweight and obese adolescents. Findings were similar for full-fat dairy products and yogurt. Higher consumption of low-fat dairy products and cheese were associated with a 46 % (prevalence ratio, PR 1·46, 95 % CI 1·18, 1·80) and 33 % (PR 1·33, 95 % CI 1·14, 1·57) higher combined prevalence of prediabetes and T2DM, respectively. The total consumption of dairy products and full-fat dairy products was associated with a lower combined prevalence of prediabetes and T2DM, while the consumption of cheese and low-fat dairy products was associated with higher combined prevalence of prediabetes and T2DM in Brazilian adolescents.

Does frequency or duration of standing breaks drive changes in glycemic response? A randomized crossover trial.

Intervention strategies to break up sitting have mostly focused on the modality (i.e., comparing different intensities and/or type of activities) and less on how frequency and duration of breaks affect health outcomes. This study compared the efficacy of different strategies to break up sitting time [i.e., high frequency, low duration standing breaks (HFLD) and low frequency, high duration standing breaks (LFHD)] in reducing postprandial glucose. Eleven sedentary and prediabetic adults (mean ± SD age = 46.8 ± 10.6 years; 73% female) participated in a cross-over trial. There were six blocks that represented all potential combinations (ordering) of the study conditions and participants were randomly assigned to a block. Each participant underwent three 7.5-h laboratory visits (1 week apart) where they engaged in either continuous sitting, HFLD, or LFHD condition while performing their usual office-related tasks. Standardized breakfast and lunch meals were provided. Postprandial mean glucose, area under the curve (AUC), and incremental area under the curve (iAUC) were evaluated using mixed models. Compared with LFHD condition, the HFLD standing breaks condition significantly lowered mean glucose by -9.94 (-14.13, -5.74) mg/dL·h after lunch, and by -6.23 (-9.93, -2.52) mg/dL·h, for the total lab visit time. Overall, the results favor frequently interrupting sitting with standing breaks to improve glycemic control in individuals with prediabetes. Further studies are needed with larger sample sizes to confirm the results.

Psychosocial and behavioral outcomes in the adult workforce during the COVID-19 pandemic: a 1-Year longitudinal survey.

BACKGROUND: Efforts to limit the spread of COVID-19 have included public space closures, mask usage, and quarantining. Studies regarding the impact of these measures on the psychosocial and behavioral health outcomes of the workforce have focused frequently on healthcare employees. To expand the literature base, we deployed a one-year longitudinal survey among mostly non-healthcare employees assessing changes in select psychosocial outcomes, health behaviors, and COVID-19-related transmission prevention behaviors and perceptions. METHODS: We deployed the CAPTURE baseline survey across eight companies from November 20, 2020-February 8, 2021. The baseline survey included questions on psychosocial outcomes, health behaviors, and COVID-19 transmission prevention behaviors, with several questions containing a retrospective component to cover the time period prior to the pandemic. Additional questions on vaccination status and social support were subsequently added, and the updated survey deployed to the same baseline participants at three, six, and 12 months after baseline survey deployment. We analyzed data descriptively and performed Friedman's and subsequent Wilcoxon-signed rank tests, as appropriate, to compare data within and between time points. RESULTS: A total of 3607, 1788, 1545, and 1687 employees completed the baseline, 3-month, 6-month, and 12-month CAPTURE surveys, respectively, with 816 employees completing all four time points. Employees reported higher stress, anxiety, fatigue, and feelings of being unsafe across all time points compared to pre-pandemic. Time spent sleeping increased initially but returned to pre-pandemic levels at follow-up. Lower rates of physical activity and higher rates of non-work screen time and alcohol consumption relative to pre-pandemic were also reported. Over 90% of employees perceived wearing a mask, physical distancing, and receiving the COVID-19 vaccine as 'moderately' or 'very important' in preventing the spread of COVID-19 across all time points. CONCLUSIONS: Relative to pre-pandemic, poorer psychosocial outcomes and worsened health behaviors were observed across all time points, with values worse at the baseline and 12-month time points when COVID-19 surges were highest. While COVID-19 prevention behaviors were consistently deemed to be important by employees, the psychosocial outcome and health behavior data suggest the potential for harmful long-term effects of the pandemic on the well-being of non-healthcare employees.

Qualitative comparative analysis of the implementation fidelity of a workplace sedentary reduction intervention.

BACKGROUND: Stand and Move at Work was a 12-month, multicomponent, peer-led (intervention delivery personnel) worksite intervention to reduce sedentary time. Although successful, the magnitude of reduced sedentary time varied by intervention worksite. The purpose of this study was to use a qualitative comparative analysis approach to examine potential explanatory factors that could distinguish higher from lower performing worksites based on reduced sedentary time. METHODS: We assessed 12-month changes in employee sedentary time objectively using accelerometers at 12 worksites. We ranked worksites based on the magnitude of change in sedentary time and categorized sites as higher vs. lower performing. Guided by the integrated-Promoting Action on Research Implementation in Health Services framework, we created an indicator of intervention fidelity related to adherence to the protocol and competence of intervention delivery personnel (i.e., implementer). We then gathered information from employee interviews and surveys as well as delivery personnel surveys. These data were aggregated, entered into a truth table (i.e., a table containing implementation construct presence or absence), and used to examine differences between higher and lower performing worksites. RESULTS: There were substantive differences in the magnitude of change in sedentary time between higher (-75.2 min/8 h workday, CI95: -93.7, -56.7) and lower (-30.3 min/8 h workday, CI95: -38.3, -22.7) performing worksites. Conditions that were present in all higher performing sites included implementation of indoor/outdoor walking route accessibility, completion of delivery personnel surveys, and worksite culture supporting breaks (i.e., adherence to protocol). A similar pattern was found for implementer willingness to continue role and employees using face-to-face interaction/stair strategies (i.e., delivery personnel competence). However, each of these factors were also present in some of the lower performing sites suggesting we were unable to identify sufficient conditions to predict program success. CONCLUSIONS: Higher intervention adherence and implementer competence is necessary for greater program success. These findings illustrate the need for future research to identify what factors may influence intervention fidelity, and in turn, effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02566317 . Registered 2 October 2015, first participant enrolled 11 January 2016.

Efficacy of the 'Stand and Move at Work' multicomponent workplace intervention to reduce sedentary time and improve cardiometabolic risk: a group randomized clinical trial.

BACKGROUND: Sedentary time is associated with chronic disease and premature mortality. We tested a multilevel workplace intervention with and without sit-stand workstations to reduce sedentary time and lower cardiometabolic risk. METHODS: Stand and Move at Work was a group (cluster) randomized trial conducted between January 2016 and December 2017 among full-time employees; ≥18 years; and in academic, industry/healthcare, and government worksites in Phoenix, Arizona and Minneapolis/St. Paul, Minnesota, USA. Eligible worksites were randomized to (a) MOVE+, a multilevel intervention targeting reduction in sedentary time and increases in light physical activity (LPA); or (b) STAND+, the MOVE+ intervention along with sit-stand workstations to allow employees to sit or stand while working. The primary endpoints were objectively-measured workplace sitting and LPA at 12 months. The secondary endpoint was a clustered cardiometabolic risk score (blood pressure, glucose, insulin, triglycerides, and HDL-cholesterol) at 12 months. RESULTS: Worksites (N = 24; academic [n = 8], industry/healthcare [n = 8], and government [n = 8] sectors) and employees (N = 630; 27 ± 8 per worksite; 45 ± 11 years of age, 74% female) were enrolled. All worksites were retained and 487 participants completed the intervention and provided data for the primary endpoint. The adjusted between arm difference in sitting at 12 months was - 59.2 (CI: - 74.6,-43.8) min per 8 h workday, favoring STAND+, and in LPA at 12 months was + 2.2 (- 0.9,5.4) min per 8 h workday. Change in the clustered metabolic risk score was small and not statistically significant, but favored STAND+. In an exploratory subgroup of 95 participants with prediabetes or diabetes, the effect sizes were larger and clinically meaningful, all favoring STAND+, including blood glucose, triglycerides, systolic blood pressure, glycated hemoglobin, LDL-cholesterol, body weight, and body fat. CONCLUSIONS: Multilevel workplace interventions that include the use of sit-stand workstations are effective for large reductions in sitting time over 12 months. Among those with prediabetes or diabetes, clinical improvements in cardiometabolic risk factors and body weight may be realized. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02566317 . Registered 2 October 2015, first participant enrolled 11 January 2016.

The effect of green walking on heart rate variability: A pilot crossover study.

We investigated the effects of regular walking in green and suburban environments on heart rate variability (HRV) and blood pressure (BP) in middle-aged adults. Twenty-three adults participated in a non-randomized crossover experiment comprised of once-weekly 50-min moderate-intensity walking sessions. Separated by a two-week washout period, participants walked for three weeks in each of two treatment conditions (green and suburban) in a local arboretum and suburban sidewalks of Chaska, MN. Eleven participants completed green walking first and 12 suburban walking first. Walks were split into 15-min intra-walk phases, with phases representing each walk's beginning, middle, and final 15-min. Repeated measures linear mixed models evaluated (1) HRV phase differences between treatments and HRV change within treatments, and (2) pre- and post-walk BP differences between treatments and pre-to post-walk BP changes. Intra-walk phase analyses revealed higher HRV during green walking vs. suburban walking during phase 2 (p < 0.0001) and phase 3 (p = 0.02). Less HRV reduction was seen between intra-walk phases 1 and 2 during green vs. suburban walking (p = 0.02). Pre-to post-walk changes revealed decreased mean systolic BP for both green (p = 0.0002) and suburban (p = 0.003) walking conditions, but not for diastolic BP. Post-walk BP results were similar after both green walking and suburban walking. In summary, walking sessions in a green environment elicited greater beneficial HRV responses compared to a suburban environment. Additionally, walking in either environment, green or suburban, promoted reductions in systolic BP.

Relationship between different levels of the Mexican food environment and dietary intake: a qualitative systematic review.

OBJECTIVE: To investigate the possible associations between the food environment and dietary intake in the Mexican population. DESIGN: Four databases (PubMed, PsychInfo, Web of Science and SCIelo) were used to retrieve relevant articles using an open timeframe. Articles were reviewed if they contained a systematic measure (i.e. food checklist) of the food environment (e.g. food availability) and dietary intake. SETTING: Urban and rural communities in Mexico. PARTICIPANTS: Population-based studies of Mexican communities. RESULTS: Twenty studies that assessed at least one food environment level, and at least one dietary outcome, were reviewed. Findings from these studies showed that changes in the Mexican food environment seem to be associated with higher availability of energy-dense foods. Energy-dense foods can be linked to a high consumption in household, environment and community food environments. When both nutrient-dense and energy-dense foods were present, individuals were more likely to consume foods with added sugars, fats and salt options than nutrient-dense items. CONCLUSIONS: The various levels of the food environment (i.e. household, school, community) exposed participants to energy-dense foods. Although nutrient-dense foods were present in all three levels, individuals were more likely to consume energy-dense food items. Not all three levels of the food environment are well represented in the urban and rural settings. Most studies on the community food environment were done in rural areas, whereas most studies on the school food environment were done in urban settings. Additional rigorously designed studies are needed to document the relationship between the food environment and dietary intake in the Mexican population.

Sedentary Behaviors and Cardiometabolic Risk: An Isotemporal Substitution Analysis.

Evidence suggests that time spent engaging in sedentary behaviors is associated with a greater risk of adverse cardiometabolic outcomes. We investigated the cross-sectional associations of 6 unique sedentary tasks (watching television, using the computer, completing paperwork, reading, talking on the telephone, and sitting in a car) with cardiometabolic risk factors, and also examined the effect of replacing one type of sedentary behavior with another on the level of cardiometabolic risk. Participants consisted of 3,211 individuals from the Coronary Artery Risk Development in Young Adults Study who visited the clinic between 2010 and 2011. Linear regression models examined the independent and joint associations of sedentary tasks with a composite cardiometabolic risk score, as well as with individual cardiometabolic risk factors (waist circumference, blood pressure, fasting glucose, insulin, triglycerides, and high density lipoprotein cholesterol) after adjusting for physical activity and other covariates. Replacing 2 hours of television viewing with 2 hours spent performing any other sedentary activity was associated with a lower cardiometabolic risk score of 0.06-0.09 standard deviations (all 95% confidence intervals: -0.13, -0.02). No other replacements of one type of sedentary task for another were significant. Study findings indicate that television viewing has a more adverse association with cardiometabolic risk factors than other sedentary behaviors.

Assessment of the accuracy of nutrient calculations of five popular nutrition tracking applications.

OBJECTIVE: To assess the accuracy of nutrient intake calculations from leading nutrition tracking applications (apps). DESIGN: Nutrient intake estimates from thirty 24 h dietary recalls collected using Nutrition Data System for Research (NDSR) were compared with intake calculations from these recalls entered by the researcher into five free nutrition tracking apps. Apps were selected from the Apple App Store based on consumer popularity from the list of free 'Health and Fitness' apps classified as a nutrition tracking apps. SUBJECTS: Dietary recall data collected from thirty lower-income adults. RESULTS: Correlations between nutrient intake calculations from NDSR and the nutrition tracking apps ranged from 0·73 to 0·96 for energy and macronutrients. Correlations for the other nutrients examined (Na, total sugars, fibre, cholesterol, saturated fat) ranged from 0·57 to 0·93. For each app, one or more mean nutrient intake calculations were significantly lower than those from NDSR. These differences included total protein (P=0·03), total fat (P=0·005), Na (P=0·02) and cholesterol (P=0·005) for MyFitnessPal; dietary fibre (P=0·04) for Fitbit; total protein (P=0·0004), total fat (P=0·008), Na (P=0·002), sugars (P=0·007), cholesterol (P=0·0006) and saturated fat (P=0·005) for Lose It!; Na (P=0·03) and dietary fibre (P=0·005) for MyPlate; and total fat (P=0·03) for Lifesum. CONCLUSIONS: Findings suggest that nutrient calculations from leading nutrition tracking apps tend to be lower than those from NDSR, a dietary analysis software developed for research purposes. Further research is needed to evaluate the validity of the apps when foods consumed are entered by consumers.

Social ecological correlates of workplace sedentary behavior.

BACKGROUND: To identify social ecological correlates of objectively measured workplace sedentary behavior. METHODS: Participants from 24 worksites - across academic, industrial, and government sectors - wore an activPAL-micro accelerometer for 7-days (Jan-Nov 2016). Work time was segmented using daily logs. Sedentary behavior outcomes included time spent sitting, standing, in light intensity physical activity (LPA, stepping cadence <100 steps/min), and in prolonged sitting bouts (>30 min). Outcomes were standardized to an 8 h work day. Two electronic surveys were completed to derive individual (job type and work engagement), cultural (lunch away from the desk, walking at lunch and face-to-face interaction), physical (personal printer and office type) and organizational (sector) factors. Mixed-model analyses with worksite-level clustering were performed to examine multi-level associations. Secondary analyses examined job type and sector as moderators of these associations. All models were adjusted for age, race/ethnicity and gender. RESULTS: Participants (N = 478; 72% female; age: 45.0 ± 11.3 years; 77.8% non-Hispanic white) wore the activPAL-micro for 90.2 ± 15.5% of the reported workday. Walking at lunch was positively associated with LPA (5.0 ± 0.5 min/8 h, P < 0.001). Regular face-to-face interaction was negatively associated with prolonged sitting (-11.3 ± 4.8 min/8 h, P < 0.05). Individuals in private offices sat more (20.1 ± 9.1 min/8 h, P < 0.05), stood less (-21.5 ± 8.8 min/8 h, P < 0.05), and engaged in more prolonged sitting (40.9 ± 11.2 min/8 h, P < 0.001) than those in public office space. These associations were further modified by job type and sector. CONCLUSIONS: Work-specific individual, cultural, physical and organizational factors are associated with workplace sedentary behavior. Associations vary by job type and sector and should be considered in the design of workplace interventions to reduce sedentary behavior. TRIAL REGISTRATION: Clinical trial No. NCT02566317 ; Registered Sept 22nd 2015.

Total and Full-Fat, but Not Low-Fat, Dairy Product Intakes are Inversely Associated with Metabolic Syndrome in Adults.

BACKGROUND: Growing evidence suggests that dairy products may have beneficial cardiometabolic effects. The current guidelines, however, limit the intake of full-fat dairy products. OBJECTIVE: We investigated the association of dairy consumption, types of dairy products, and dairy fat content with metabolic syndrome (MetSyn). METHODS: We analyzed baseline data of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multicenter cohort study of 15,105 adults aged 35-74 y. We excluded participants with known diabetes, cardiovascular diseases, or other chronic diseases, and those who had extreme values of energy intake, leaving 9835 for analysis. Dairy consumption was assessed by a food-frequency questionnaire. We computed servings per day for total and subgroups of dairy intake. We computed a metabolic risk score (MetScore) as the mean z score of waist circumference, systolic blood pressure, HDL cholesterol (negative z score), fasting triglycerides, and fasting glucose. We performed multivariable linear regression to test the association of servings per day of dairy products with MetScore. RESULTS: In analyses that adjusted for demographics, menopausal status, family history of diabetes, dietary intake, nondietary lifestyle factors, and body mass index, we observed a graded inverse association for MetScore with total dairy (-0.044 ± 0.01, P = 0.009 for each additional dairy servings per day) and full-fat dairy (-0.126 ± 0.03, P < 0.001) but not with low-fat dairy intake. Associations were no longer present after additional adjustments for dairy-derived saturated fatty acids. CONCLUSIONS: Total and especially full-fat dairy food intakes are inversely and independently associated with metabolic syndrome in middle-aged and older adults, associations that seem to be mediated by dairy saturated fatty acids. Dietary recommendations to avoid full-fat dairy intake are not supported by our findings.

Is There a Relationship Between Perceived Neighborhood Contentedness and Physical Activity in Young Men and Women.

The relationship between perceived neighborhood contentedness and physical activity was evaluated in the Add Health study population. Wave I includes 20,745 respondents (collected between 1994 and 1995) and wave II includes 14,738 (71 %) of these same students (collected in 1996). Multinomial logistic regression was used to evaluate this relationship in both wave I and wave II of the sample. Higher levels of Perceived Neighborhood Contentedness were associated with higher reports of physical activity in both males and females and in both waves. For every one-point increment in PNS, males were 1.3 times as likely to report being highly physically active than low (95 % CI 1.23-1.37) in wave 1 and 1.25 times as likely in wave 2 (95 % CI 1.17-1.33). Females were 1.17 (95 % CI 1.12-1.22) times as likely to report being highly active than low and 1.22 times as likely in wave 2 (95 % CI 1.17-1.27) with every one-point increment. PNC appears to be significantly associated with physical activity in adolescents. Involving the community in the development of intervention programs could help to raise the contentedness of adolescents in these communities.

Nutritional status and body composition in patients with peripheral arterial disease: A cross-sectional examination of disease severity and quality of life.

Nutritional and body weight recommendations for cardiovascular diseases are well established, yet there are no equivalent guidelines for peripheral arterial disease (PAD). This cross-sectional study measured the prevalence of cardiovascular-related nutritional and body composition risk factors in sixty PAD patients and their association with PAD severity. A diet that exceeds daily recommended intake of fat and that falls short of recommended intakes of fiber, folate, and vitamin D was associated with increased leg pain and walking difficulty. Increased body fat and waist circumference were associated with diminished walking ability and poorer psychosocial quality of life. Future prospective investigations are merited to inform both PAD clinical care and disease management guidelines.

Leg length and type 2 diabetes: what's the link?

PURPOSE OF REVIEW: Human leg length is determined by a complex interplay of genetics and environmental exposures during development, which may be associated with long-term metabolic disease risk. Here, we review recent literature on the link between relative leg length and type 2 diabetes in more and less economically developed societies, wherein the contextual influences on relative leg length are unique. We also hypothesize mechanisms underlying and mediating this association. RECENT FINDINGS: Evidence from more economically prosperous Western populations and contemporary adult populations in China and Brazil indicates that lower relative leg length is associated with greater risk for impaired glucose homeostasis and type 2 diabetes. In Brazil, this association was stronger among women with early menarche. Although still poorly defined and in need of further research, the potential mechanisms likely involve suboptimal early-life net nutrition that simultaneously leads to retarded growth and impaired glucose regulation. An untested hypothesis is that the association is mediated by differences in skeletal muscle mass. SUMMARY: Epidemiologic evidence from diverse settings points to humans with shorter legs relative to their stature having higher risk for type 2 diabetes. Although research is needed to test mechanistic hypotheses, the greatest potential for improving public health will come through identification of, and intervention upon, the upstream modifiable determinants of inadequate leg growth.

Beverage habits and mortality in Chinese adults.

BACKGROUND: There is limited research examining beverage habits, one of the most habitual dietary behaviors, with mortality risk. OBJECTIVE: This study examined the association between coffee, black and green tea, sugar-sweetened beverages (soft drinks and juice), and alcohol and all-cause and cause-specific mortality. METHODS: A prospective data analysis was conducted with the use of the Singapore Chinese Health Study, including 52,584 Chinese men and women (aged 45-74 y) free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. Beverages were examined with all-cause and cause-specific (cancer, CVD, and respiratory disease) mortality risk with the use of Cox proportional hazards regression. RESULTS: The associations between coffee, black tea, and alcohol intake and all-cause mortality were modified by smoking status. Among never-smokers there was an inverse dose-response association between higher amounts of coffee and black tea intake and all-cause, respiratory-related, and CVD mortality (black tea only). The fully adjusted HRs for all-cause mortality for coffee for <1/d, 1/d, and ≥2/d relative to no coffee intake were 0.89, 0.86, and 0.83, respectively (P-trend = 0.0003). For the same black tea categories the HRs were 0.95, 0.90, and 0.72, respectively (P-trend = 0.0005). Among ever-smokers there was no association between coffee or black tea and the outcomes. Relative to no alcohol, light to moderate intake was inversely associated with all-cause mortality (HR: 0.87; 95% CI: 0.79, 0.96) in never-smokers with a similar magnitude of association in ever-smokers. There was no association between heavy alcohol intake and all-cause mortality in never-smokers and a strong positive association in ever-smokers (HR: 1.56; 95% CI: 1.40, 1.74). Green tea and sugar-sweetened beverages were not associated with all-cause or cause-specific mortality. CONCLUSIONS: Higher coffee and black tea intake was inversely associated with mortality in never-smokers, light to moderate alcohol intake was inversely associated with mortality regardless of smoking status, heavy alcohol intake was positively associated with mortality in ever-smokers, and there was no association between sugar-sweetened beverages and green tea and mortality.

Earlier age at menarche is associated with higher diabetes risk and cardiometabolic disease risk factors in Brazilian adults: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

OBJECTIVES: Early menarche has been linked to higher risk of type 2 diabetes in Western and Asian societies, yet whether age at menarche is associated with diabetes in Latin America, where puberty and diabetes may have different life courses, is unknown. We tested the hypothesis that earlier menarche is associated with higher diabetes risk in Brazilian adults. METHODS: We used data from 8,075 women aged 35-74 years in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had complete information on age at menarche, diabetes status, and covariates. Diabetes was defined based on self-reported physician diagnosis, medication use, and laboratory variables (fasting glucose, 2-hour glucose, and glycated hemoglobin). Poisson regression was used to generate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Menarche onset < 11 years [vs. 13-14 years (referent)] was associated with higher risk of diabetes (RR = 1.34; 95% CI: 1.14-1.57) after adjusting for sociodemographic factors, maternal education, maternal and paternal diabetes, and birth weight. This persisted after further control for BMI at age 20 years and relative leg length. Additionally, among those not taking diabetes medications, earlier menarche [<11 years vs. 13-14 years (referent)] was associated with higher % glycated hemoglobin (p < 0.001), alanine aminotransferase (p < 0.001), triglycerides (p < 0.001), C-reactive protein (p = 0.003), waist circumference (p < 0.001), and BMI measured at baseline exam (p < 0.001). CONCLUSION: These findings support the hypothesis that earlier menarche is associated with greater risk for adult diabetes and cardiometabolic disease in the Brazilian context.

Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion.

Multidrug resistance (MDR) remains one of the major obstacles in chemotherapy, potentially rendering a multitude of drugs ineffective. Previously, we have demonstrated that mitochondrial targeting of DNA damaging agents is a promising tool for evading a number of common resistance factors that are present in the nucleus or cytosol. In particular, mitochondria-targeted chlorambucil (mt-Cbl) has increased potency and activity against resistant cancer cells compared to the parent compound chlorambucil (Cbl). However, it was found that, due to its high reactivity, mt-Cbl induces a necrotic type of cell death via rapid nonspecific alkylation of mitochondrial proteins. Here, we demonstrate that by tuning the alkylating activity of mt-Cbl via chemical modification, the rate of generation of protein adducts can be reduced, resulting in a shift of the cell death mechanism from necrosis to a more controlled apoptotic pathway. Moreover, we demonstrate that all of the modified mt-Cbl compounds effectively evade MDR resulting from cytosolic GST-µ upregulation by rapidly accumulating in mitochondria, inducing cell death directly from within. In this study, we systematically elucidated the advantages and limitations of targeting alkylating agents with varying reactivity to mitochondria.